In the U.S., about 1 in 300 live births carry a trisomy, roughly half of which are trisomy for chromosome 21 (Chr21), which causes Down syndrome (DS). DS is the leading genetic cause of cognitive disability with increasing prevalence, and millions of patients worldwide experience congenital and progressive medical issues that impact multiple organ systems1,2. In addition to progressive intellectual impairment and early onset Alzheimer disease, there is greatly increased risk of myeloproliferative disorder, childhood leukemia, heart defects, and both immune and endocrine system dysfunction. DS researchers have sought to define the more “DS critical” genes on Chr21, but this has proven difficult due to high genetic complexity and phenotypic variability of DS, confounded by normal variation between any individuals1-3. Much progress has been made in developing DS mouse models4-6, however there remains a critical need for better ways to understand the underlying cell and developmental pathology of human DS, so key to rationale design of therapeutics of any kind7.
The last decade has seen great advances in strategies to correct single-gene defects of rare monogenic disorders, beginning with cells in vitro and in several cases advancing to in vivo and clinical trials. In contrast, genetic correction of the over-dose of genes across a whole extra chromosome in trisomic cells has remained outside the realm of possibility.